CN101553160A - Non-invasive glucose sensor - Google Patents

Non-invasive glucose sensor Download PDF

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CN101553160A
CN101553160A CNA2007800141370A CN200780014137A CN101553160A CN 101553160 A CN101553160 A CN 101553160A CN A2007800141370 A CNA2007800141370 A CN A2007800141370A CN 200780014137 A CN200780014137 A CN 200780014137A CN 101553160 A CN101553160 A CN 101553160A
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blood
glucose
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M·范赫佩恩
O·祖赫
G·冯-巴苏姆
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Philips Intellectual Property and Standards GmbH
Koninklijke Philips NV
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters

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Abstract

Apparatus and method for sensing HO activity, and in particular blood glucose level based on an analyte level determination, the analyte being carboxyhemoglobin. In a preferred embodiment, HO activity and/or blood glucose level are extrapolated from Hb-CO level by determining an intermediate CO level. The apparatus and method are preferably non invasive.

Description

Non-invasive glucose sensor
The present invention relates to be used for measuring the instrument and the method for blood analyte level, and relate more specifically to be used for the instrument and the method for non-invasive measurement blood glucose levels.
Diabetes relate to regulate the disease that the biological mechanism of glucemia (being concentration of glucose in the blood) lost efficacy.For at auxiliary adjustment blood glucose in the daytime, and for reduce numerous physiological problems that may take place diabetics-comprising especially in eye as retinopathy, uvea metabolic pathological changes or cataractous concurrency degeneration pathological changes, as far as possible frequent monitoring of blood glucose level.This monitoring needs and what measures insulin injection with to be absolutely necessary for auxiliary determining when.Thereby pressing for non-invasive glucose sensor to increase correct monitoring patient's frequency, the patient will not need one to use the finger pricker for several times, because this operation causes suffering and be the potential source of infection.
The different system of non-invasive monitoring blood-glucose has been proposed.Described system depends on spectral technique usually; usually based on the absorption of glucose in infrared/mid infrared region, use one or more wavelength to shine sampling tissue (normally have a large amount of blood vessels and do not have body part such as the finger tip or the ear-lobe of too many skin layer).Collect and analyze intensity of reflected light and/or transmitted intensity, and calculate glucose level based on absorbance data and collected spectrum.This pick off based near infrared spectroscopy is at U.S. Patent number 4,655, describes in 225, and wherein blood-glucose is measured by analyzing transmission and carried out through the infrared light of finger.The scope of light source is 1000-2500nm, and blood glucose levels uses two kinds of preferred wavelength to measure.
Yet other numerous materials has intensive spectrum characteristic on the wavelength that is used for the perception glucose.These molecules Ru Shui, salt or fat thereby may disturb the measurement of glucose level are because of the overlapped spectra band of total material causes poor selectivity.The spectrum of high superposed need use multivariate calibration mathematics and the numerous correction spectrum of data, can extract the model of the dependency glucose information that is submerged in the out of Memory with relevant dextrose equivalent exploitation.
In addition, the degree of accuracy of current non-invasive glucose sensor is generally about 1.6mmol/L, and preferred degree of accuracy is the 1mmol/L rank.Therefore, need the selectivity and the sensitivity of improvement to be used for non-invasive glucose measurement.
Purpose of the present invention thereby provide is used for non-invasively measuring with reliable and accurate way the instrument and the method for blood glucose levels.
The invention discloses the instrument that is used to measure heme oxygenase enzymatic activity and/or blood glucose levels, this instrument comprises: be used to measure the CO determinator that the blood of the CO level that blood produces produces and be used for inferring according to the CO level that described blood produces first apparatus for predicting of the active and/or described blood glucose levels of described HO.
The present invention proposes to measure HO activity and/or blood glucose levels by blood CO.Correct deduction can produce the value of active value of HO and blood glucose levels.
Carboxyhemoglobin is the stable compound that interacts and produce because of carbon monoxide (CO) and hemoglobin.Hemoglobin to the affinity of carbon monoxide than it to high about 240 times of the affinity of oxygen, this meaning CO combines the oxygen supply that oxygen is dissociated and deprive tissue competitively with the hemoglobin of carrying oxygen.Therefore, CO is a toxic gas, they are a large amount of suck cause stupor, headache, subsequently weak (serious weakness) also finally die of asphyxiation.
Hb-CO can dissociate in lung, discharges the CO molecule to expiration.
In addition, also endogenous generation in human body of CO.The main source of CO is that the disintegrate of enzymatic haemachrome becomes biliverdin, and this is caused by Heme oxygenase-1 (HO-1).This reaction has three kinds of products: bilirubin, CO and ferritin, and the CO that produces in the haemachrome disintegrate combines the formation carboxyhemoglobin with hemoglobin.The amount of the CO that endogenous produces in the inherent health of scope preset time will be called the CO that blood produces.
Therefore, the CO in the expiration can be included in the CO that produces in the haemachrome disintegrate, and from the dissociated CO of Hb-CO in the lung.
Thereby, the CO that in breathing, measures amount and the horizontal direct correlation of blood Hb-CO, wherein blood Hb-CO level then is to absorbing the tolerance of the CO amount to the blood flow.Because blood CO comprises the CO that blood produces, and since the haemachrome disintegrate cause because of Heme oxygenase, so the amount of blood CO can with blood Hb-CO and related with the HO activity.
In addition, studied influence (the Paredi P of diabetes to the CO level of exhalation, Biernacki W, Invernizzi G, Kharitonov SA, Barnes P, " Exhaled carbonmonoxide levels elevated in diabetes and correlated with glucose concentrationin blood ", Chest 116 (4), 1007-1011 (1999)).The CO level of breathing out in finding to breathe is higher in diabetics, and may produce relatedness between CO that breathes out and blood glucose levels.In oral glucose tolerance test (OGTT), the increase of the increase of blood glucose levels (from 3.9 to 5.5mmol/L) and the CO that breathes out (from 3.0 to 6.3ppm) is relevant.
This contact can be explained by different factors, activate (R.Henningsson as Heme oxygenase because of glucose, P.Alm, P.Ekstroem, I.Lundquist, " Heme Oxygenase andCarbon Monoxide:Regulatory Roles in Islet Hormone Release ", Diabetes 48,66-77 (1999)) and CO to the positive control of insulin secretion, thereby rapid CO level increase may be to reply that glucose level changes and the part of the counter regulation mechanism that is activated.It also can be reply hyperglycemia the reflection of HO enzyme activation under the inductive oxidative stress.Therefore, the activation of HO enzyme causes the CO that is produced by the haemachrome disintegrate to increase, and therefore causes the increase of the CO that breathes out.
Generally speaking, between Heme oxygenase and the CO get in touch can be by the model explanation of (simplification) shown in Fig. 1.
For example, at first there is the little change of blood-glucose value.This has activated the Heme oxygenase (HO) (arrow 1 in Fig. 1) that haemachrome is resolved into bilirubin, CO and ferritin.
Therefore formed CO molecule can combine with hemoglobin (Hb) rapidly to form Hb-CO (arrow 2 in Fig. 1).Hemoglobin to the affinity of carbon monoxide than it to high about 240 times of the affinity of oxygen, this makes this process very rapid.Expect that whole CO can combine with Hb-CO rapidly, after this as Hb-CO during in the lung internal disintegration, CO is slowly discharged and breathe out (arrow 3 in Fig. 1).
Yet, possible portion C O can with from lung, escape before Hb-CO combines (arrow 4 in Fig. 1).
Thereby, from CO poisons research, know first relatedness between the blood Hb-CO level and CO level in the breathing of exhalation, and verified second relatedness of diabetes study in expiration described CO level and blood glucose levels between exist.The present invention proposes to utilize aforementioned these two kinds of contacts, and this combination results is from described blood Hb-CO level with breathe the CO level the active novel deduction method of HO.HO shows antiinflammatory, anti-apoptosis and antiproliferative function, and its beneficial effect is described in the multiple disease as atherosclerosis and preceding-eclamposia now: monitoring HO activity is auxiliary a kind of approach of understanding this enzyme so as to the mechanism of generation protective effect.
In addition, this combination also produces the favourable mensuration to blood glucose levels that allows continuous monitoring.Blood glucose levels must often be monitored as much as possible, so as auxiliary adjustment in the daytime glucemia and for reduce numerous physiological problems that may take place diabetics-comprising especially in eye as retinopathy, uvea metabolic pathological changes or cataractous concurrency degeneration pathological changes.This monitoring needs and what measures insulin injection with to be absolutely necessary for auxiliary determining when.
In exemplary of the present invention, can from the CO level that blood produces, infer HO activity and/or blood glucose levels, wherein produce so hypothesis, the CO that has promptly only produced in the preset time scope in health and escaped in lung can be related with glucose, and represented the background signal in the measurement result from the dissociated CO of Hb-CO.
In fact, Hb-CO has utmost point half life slowly, and this meaning CO only can discharge in expiration lentamente.Hb-CO can represent general environment such as city or the rural area that wherein environment CO level is different so blood CO level is different, and the meansigma methods of representing any CO change effect.
Therefore, by CO determinator and the apparatus for predicting that provides blood to produce, can measure HO activity and glucose level.In this method, suppose all or much at one share directly discharge in lung from the CO of haemachrome disintegrate, do not combine, and can be related with heme oxygenase enzymatic activity and glucose with hemoglobin.
According to concrete aspect of the present invention, the CO determinator that described blood produces comprises the breathing CO sensing device that is used for perception breathing CO level, the Hb-CO sensing device that is used for perception blood carboxyhemoglobin (Hb-CO) level is inferred the horizontal apparatus for predicting of CO that the blood of the CO level that described blood produces produces with being used for according to described Hb-CO level and described exhalation CO level.
In fact, always breathe that CO comprises CO that described blood produces and combine with hemoglobin and form the described CO of Hb-CO.Therefore, breathe the CO sensing device, can measure the breathing CO level in the breathing by providing.Similarly, by Hb-CO is provided sensing device, can measure blood carboxyhemoglobin (Hb-CO) level.The CO that described blood produces can be inferred as the function of Hb-CO level and the function of breathing level subsequently.
Therefore, the horizontal apparatus for predicting of CO of described blood generation can also comprise the CO accountant that is used for calculating according to described blood Hb-CO level the CO level of calculating.With the amount of the CO of expiratory measurements change into blood Hb-CO level (" carboxyhemoglobin level ", Http:// www.indsci.com/docs/Gas_Carboxy_Intrinsic.pdf) relational expression be well-known, especially when research CO poisons.By the accountant that is suitable for calculating the CO level is provided, can be from the blood Hb-CO level of perception derivation CO level.The CO level that will be called calculating from this CO level of blood Hb-CO deduction.
For example, described breathing CO sensing device is suitable for measuring the CO level of suction and the CO level of exhalation.In fact, the amount of the CO of exhalation depends on the amount of Hb-CO as previously mentioned and depends on the amount of the CO that blood produces.In addition, the CO that has sucked also can breathe out again at least in part.Therefore, the CO sensing device of the CO level by the CO level that is suitable for measuring suction and exhalation are provided can be considered the whole contribution factors to CO exhalation level, and measure can be more accurate.
In one embodiment, described breathing CO sensing device is an optical gas sensor.This pick off for example can use directly absorption spectroscopy, photoacoustic spectroscopy, optical cavity ring-down spectroscopy or optical cavity leakage spectroscopy (cavity leak-out spectroscopy).
Therefore, the CO level that produces of described blood is the function of the CO level of the CO level of the CO level of described exhalation, described suction and described calculating.
The present invention also openly is used to measure the instrument of heme oxygenase enzymatic activity and/or blood glucose levels, and this instrument comprises the Hb-CO sensing device that is used for perception blood carboxyhemoglobin (Hb-CO) level and is used for inferring according to described Hb-CO level second apparatus for predicting of described HO activity and/or described blood glucose levels.
Can be undertaken by analyte level mensuration blood glucose levels and/or the active mensuration of HO, described analyte is carboxyhemoglobin (Hb-CO).Correct deduction can produce blood glucose levels and/or the active value of HO.
Refer again to Fig. 1 and explain getting in touch between Heme oxygenase and the carbon monoxide.The little change activation Heme oxygenase of blood glucose levels, thereby cause the haemachrome disintegrate.Formed CO molecule can partly combine with hemoglobin, forms Hb-CO, wherein Hb-CO disintegrate and discharge CO in lung.From CO poisons research, know the relatedness between the blood Hb-CO level and CO level in the expiration, and verified second relatedness of diabetes study in expiration described CO level and blood glucose levels between exist.Second embodiment preferred of the present invention proposes to utilize these contacts, and this combination produces the novel deduction method of active to HO in blood glucose levels from described blood Hb-CO level in very favourable mode.
Therefore, by the instrument that comprises Hb-CO sensing device and glucose level apparatus for predicting is provided, can be in first step perception blood Hb-CO level, thereby based on the blood Hb-CO level of described perception and measure blood glucose levels and/or HO activity.
In one embodiment, described second apparatus for predicting comprises the CO level calculation device that is used for calculating according to described Hb-CO level carbon monoxide level.In addition, described second apparatus for predicting also comprises the glucose level accountant that is used for calculating according to the CO level of described calculating described blood glucose levels.
CO by being provided at exhalation and the first deduction method between the Hb-CO, the CO level can be calculated by described CO level calculation device, and in a similar manner, the glucose level accountant can use the CO of exhalation and the deduction method between the blood glucose levels and calculate described blood glucose levels.
In addition, instrument of the present invention can comprise and is used for calculating the CO level correction device that described glucose level comprises environment CO level according to described CO level.
In fact, according to general environment, environment CO level can be different, therefore influence blood CO level.For example, blood CO level can maybe may depend on pollution level than higher in the rural area in the city, and depends on other extraneous factor.Because the deduction of blood glucose levels is depended on from the Hb-CO level the single deduction of CO level, and the blood glucose levels of described deduction can drift about because of described environment CO level.Thereby, will consider that environment CO level produces right value with the deduction of guaranteeing blood glucose levels.
In exemplary, described CO level correction device can comprise CO sensing device that is used for perception environment CO level and the model building device that is used for the Hb-CO level that responds to described environment CO level is carried out modeling.Therefore, by being provided for calculating the model building device that changes because of the Hb-CO level of environment CO level due to changing, and may depend on other parameter, as heart rate, breathing rate and other parameter, can improve the degree of accuracy that glucose level is measured, maybe can increase the time between the correction.
Most preferably, described Hb-CO sensing device right and wrong are invasive.Developed numerous invasives and Noninvasive hemoglobin sensor (comprising hemoglobin complex such as carboxyhemoglobin, oxygen hemoglobin, deoxyhemoglobin), especially be intended to detect CO and poison.By preferably using Noninvasive Hb-CO sensing device, the repeatedly Noninvasive blood-glucose perception instrument of perception blood glucose levels of the utmost point might be provided by day, needn't stand the inconvenience of invasive glucose detector.
Instrument of the present invention can also comprise the correcting unit that is used to proofread and correct the active and/or described blood glucose levels of the described HO that is obtained by deduction.
In fact, when HO activity and/or blood glucose levels when the direct measurement of Hb-CO is measured, this measurement can be influenced by different parameters, can audient's multiparameter and physiological function (asthma, hypertension, sepsis or preceding-eclamposia are wherein arranged) influence (D.Morse as blood Hb-CO level, A.M.K.Choi, " Heme Oxygenase-1.The ' Emerging Molecule " Has Arrived ", Am.J.Respir.Cell Mol.Biol.27,8-16 (2002)).The glucose level of inferring can drift about because of current Hb-CO level.Thereby, instrument of the present invention preferably comprise the glucose level correcting unit so as to proofread and correct Hb-CO and glucose between get in touch activity with HO.
When the CO level determination blood glucose levels that produces according to blood, dissimilar carbon monoxides is able to perception and calculates, and therefore may cause during inferring and depart from true blood glucose levels.And it happens frequently when using different deduction method, may must proofread and correct to improve the degree of accuracy of blood glucose levels measurement therefore.Because the amount direct correlation of the CO that the HO activity can produce with described blood is so correction can be required really.
Described correcting unit can comprise at least a reference glucose sensing device that is used for perception reference glucose level, and/or is used for the described blood glucose levels that comparison obtains on the time at different measuring and/or the comparison means of the active value of described HO.
Conceived dissimilar corrections.A kind of selection is to use reference glucose sensing device with perception reference glucose level.In this case, correcting unit can be suitable for perception reference glucose level and the glucose level of described deduction is adjusted to described reference glucose level.
Another kind of choosing then may rely on comparison means, and described comparison means is used for described blood glucose levels and/or the active value of described HO that comparison obtained in the different measuring time.
Depend on user's needs and depend on and detect which kind of object (heme oxygenase enzymatic activity and/or blood glucose levels) that correcting unit can comprise one of both of the mentioned correction option in front or both.
Described glucose level correcting unit can revise so that perception reference glucose level and based on the rule time, may be based on every day and the glucose level of described deduction is adjusted to described reference glucose level.
And especially when directly measuring blood glucose levels according to the blood Hb-CO of perception, different parameters can influence this measurement, because blood Hb-CO level may audient's multiparameter and physiological function influence in fact.These other physiological functions that influence blood Hb-CO level generally cause the Hb-CO level slowly to change in time.Thereby, behind certain time quantum, consider glucose measurements is proofreaied and correct again.This correction will preferably be carried out based on the rule time (for example once a day).
On the other hand, when the CO level determination blood glucose levels that produces according to blood, also may need to proofread and correct, because make such hypothesis, promptly always the CO of the generation of same percentage can directly escape from lung.This share may for example change according to general environment, and wherein environment CO influences the level of blood Hb-CO, and influences the level of hemoglobin subsequently.Yet, should also be pointed out that the background measurement result of in this case blood Hb-CO being regarded as to blood CO.
In one embodiment, described reference glucose sensing device is a fingerstick type glucose sensor, and it shows needed clear and definite degree of accuracy of reference and performance.
In one embodiment, described comparison means is suitable for carry out at least a following comparison: ratio, the different measuring time of the CO of the ratio of CO that the active value of described HO, described blood produce and described breathing CO, the CO that described blood produces and described calculating are gone up described value and the ratio that obtains.
In fact, in order to monitor potential disease such as diabetes, comparison means can be as monitoring the device that different parameters develops in time with the reference measurement result, and wherein said reference measurement result can produce on different time with another kind of pick off or with identical pick off.
Described Hb-CO sensing device can be suitable for providing the perception degree of accuracy of 0.5%Hb-CO at least.In fact, the change of the CO that the corresponding 3.3ppm of the change that the analysis showed that the 1.6mmol/L blood glucose levels of deduction data mentioned above is breathed out, this is corresponding with about 0.53%Hb-CO again.Thereby Noninvasive Hb-CO detector has needs and is better than about 0.5% degree of accuracy.Preferred glucose degree of accuracy is 1mmol/L, and this is corresponding to 0.3% Hb-CO degree of accuracy.Should be understood that the accurate absolute value that does not need to measure blood Hb-CO level, because the mensuration of blood-glucose obtains proofreading and correct, but the repeatability of measuring is very important.
Based on absorbing and, can using numerous different Noninvasive carboxyhemoglobin pick offs based on the spectrum characteristic of Hb-CO.
Therefore, in one embodiment of the invention, described Hb-CO sensing device can comprise: be used for a plurality of wavelength illumination sampling tissues irradiation unit, be used to collect transillumination and/or catoptrical gathering-device and be used to calculate Hb-CO accountant with transmission, emission and/or the corresponding Hb-CO level of intensity of reflected light.
Conceived to based on the similar technology of the oximetry of absorbance data.Oximetry is the technology that is used for measuring hemoglobin level, the absorbance that increases during the pulsating flow of this commercial measurement when the tremulous pulse bed is expanded because of the systole capacity increases.Usually, oximeter is measured the light transmission of process sampling tissue on different wave length.Because different hemoglobin complex (oxygenated haemoglobin, reduced hemoglobin and carboxyhemoglobin) does not have identical absorption spectrum, their concentration can be measured from relative absorption on different wave length.
Alternatively, described Hb-CO sensing device can comprise: be used for a plurality of wavelength illumination sampling tissues irradiation unit, be used to collect transillumination and/or catoptrical gathering-device, be used for according to separating transillumination/catoptrical light-dividing device from the band of described a plurality of wavelength and being used for calculating the Hb-CO accountant of described Hb-CO level according to isolating transmitted intensity and/or intensity of reflected light.
Therefore, conceived spectral measurement methods and interfere measurement technique, wherein the Hb-CO level can be measured by signal light intensity.Cognition technology can comprise Raman spectroscopy, photoacoustic spectroscopy, direct absorption spectroscopy, fluorescence spectroscopy, optical coherence tomography, thermal emission spectroscopy and the spectroscopy that diffuses.When using interferometry when (as in optical coherence tomography), light source is divided at least 2 bundles, promptly reference beam and detection bundle are surveyed Shu Tongchang and are reflected on sampling tissue.After advancing, survey bundle and reference beam and converge again, and can obtain to have the interference of the feature that depends on sampling tissue characteristic and composition through different paths.Preferred instrument can use Michelson or the measurement of Mach-Zender interferometer to come the luminous reflectance of self-organizing.
When using different excitation wavelengths and/or signal wavelength, obtain satisfied result, improved measuring accuracy.
Described a plurality of wavelength is that carboxyhemoglobin has the most intensive absorption in this scope in the about 1900nm scope of about 450nm-.Described a plurality of wavelength can comprise the wavelength of any number, and preferably at least 3 kinds or more kinds of wavelength are to improve reliability and degree of accuracy.
Described irradiation unit can comprise light source, and light emitting diode, laser, halogen light source or any other light source are wherein arranged.Considered the light source that bandwidth and coherence are different, especially white light source, broadband or monochromater.Under latter event, multiplex machine can also connect so that the single illumination beam to tissue to be provided.In addition, described irradiation unit can also comprise and be used for focused ray and guide the image optics instrument of light to sampling tissue, comprises one or more lens, guiding device, reflector or focusing arrangement.
Suitable gathering-device and light-dividing device can comprise the detector with the detection window in described a plurality of wave-length coverages, as photodiode or avalanche photodide, integrating sphere, photometer, or any suitable optoelectronics parts, wavelength select instrument, spectroanalysis instrument, spectrometer, and its resolution can be several nanometers in the defined gamut of described a plurality of wavelength.Preferably, detector has uniform sensitivity in wave-length coverage.
In addition, described gathering-device also can comprise be used for demultiplexing the demultiplexing device of different wave length glazed thread, be used to amplify perceptual signal amplifying device, in wave-length coverage, have evenly or the filter of definite response.
Accountant comprises filtering well-known in the art, signal processing apparatus and technology.
In addition, should be understood that and to use independent optics (free optics) or integrated optical device (integrated optics), for example optical fiber.
Usually, sampling tissue is the abundant tissue of blood, as finger or ear-lobe.
The tissue of another kind of special concern is a retina, because the Hb-CO level in the retina measured can provide because of the prompting of the risk of retinal damage due to the diabetes or provide the prompting of screening diabetes.Retina glucose sensor of the present invention can use the reflectance spectrum technology.When in eye, measuring, must consider the transparency of eye.Yet there is intensive spectroscopy feature in Hb-CO in the 400-900nm scope.
Therefore, the present invention also proposes to be used to measure the method for heme oxygenase enzymatic activity and/or blood glucose levels, comprises the CO level of mensuration blood generation and infers the step of described heme oxygenase enzymatic activity and/or described glucose level according to the CO level that described blood produces.
The step of inferring described heme oxygenase enzymatic activity and/or described glucose level comprises the following steps: that perception breathes CO level, perception blood carboxyhemoglobin (Hb-CO) level in breathing and infer the CO that the active and/or described blood of described HO produces according to described Hb-CO level and described breathing CO level.
In one embodiment, in the step of inferring described heme oxygenase enzymatic activity and/or described glucose level, the step that the CO level is breathed in perception comprises the CO level of perception exhalation and the CO level of suction, the step of inferring the CO level that described blood produces comprises the step of calculating carbon monoxide (CO) level according to described Hb-CO level, and the CO that wherein said blood produces is the function of the CO level of the CO level of the CO level of described calculating, described exhalation, described suction.
The present invention also is provided for non-invasively measuring the method for HO activity and/or blood glucose levels, comprises step: perception blood carboxyhemoglobin (Hb-CO) level is also inferred the active and/or described glucose level of described HO according to described Hb-CO level.
Infer that described HO step active and/or described glucose level comprises step: calculate carbon monoxide (CO) level and calculate described glucose level according to the CO level of described calculating according to described Hb-CO level.
Method of the present invention can also comprise described glucose level and/or the active step of described HO that correction is obtained by the deduction method.The step of perception blood Hb-CO is can right and wrong invasive.
At last, the invention provides be used for according to claim 22-24,27-28 each, use claim 1-6, each described instrument of 12-21, and/or according to claim 25-28 each, use claim each described instrument of 7-21 and Noninvasive is measured the method for heme oxygenase enzymatic activity and/or blood glucose levels.
Further feature of the present invention and advantage will be from hereinafter to as an example the explanations of preferred embodiment only and become apparent with reference to the accompanying drawings, wherein:
Fig. 1 explains the sketch map of Heme oxygenase and carbon monoxide between getting in touch useful to the present invention.
Fig. 2 is first preferred embodiment according to the present invention, is used to measure the functional diagram of the instrument of HO activity and/or blood glucose levels.
Fig. 3 is second preferred embodiment according to the present invention, is used to measure the functional diagram of the instrument of HO activity and/or blood glucose levels.
Fig. 4 is the sketch map that is adapted at being used for measuring the carboxyhemoglobin pick off that the instrument of HO activity and/or blood glucose levels uses according to the present invention.
Fig. 5 is the view of another kind of carboxyhemoglobin pick off that is used for measuring the instrument of HO activity and/or blood glucose levels in alternative embodiment of the present invention.
In the drawings, identical Reference numeral refers to similar parts.
Fig. 2 is first preferred embodiment according to the present invention, is used to measure the functional diagram of the instrument of HO activity and/or blood glucose levels.
This instrument comprises the CO determinator that blood produces, measure the CO that blood produces thus, the CO that described blood produces is defined as the amount of the CO that is produced in scope preset time (for example because of the intravital haemachrome disintegrate of patient), and apparatus for predicting 80 is used for inferring HO activity and/or blood glucose levels according to the CO that described blood produces.
The CO determinator that described blood produces comprises the CO apparatus for predicting 60 of breathing CO sensing device 50, Hb-CO sensing device 10, blood generation.
Breathe CO sensing device 50 and can be suitable for measuring the air-breathing of patient and expiration.Preferably, breathe CO sensing device 50 trachea 52 be housed, wherein the patient to the small part breath stream through described trachea.When the patient was air-breathing, gas was away from breathing CO sensing device 50, and when the patient exhaled, gas was advanced to breathing CO sensing device 50.By this way, can measure air-breathing and exhale in CO concentration.
Breathe CO sensing device 50 and for example can be to use the directly optical gas sensor of absorption spectroscopy, photoacoustic spectroscopy, cavity ring-down spectroscopy or optical cavity leakage spectroscopy (CALOS).
This instrument also comprises Hb-CO sensing device 10, and it is suitable for measuring blood Hb-CO level, and preferably uses the Noninvasive pick off of absorption and/or spectral technique.The preferred embodiment of Hb-CO sensing device will be described in more detail with reference to Figure 4 and 5.
Handle by the CO apparatus for predicting 60 that blood produces from the data of breathing CO sensing device 50 and Hb-CO sensing device 10.At first, CO accountant 62 is according to described Hb-CO level, uses well-known deduction method between CO and Hb-CO level and calculates the CO level.Subsequently, the CO level of described blood generation uses the CO level value, the CO level value of exhalation and the CO level value of calculating that suck to be measured.
By the CO level that described blood produces, can calculate HO activity and blood glucose levels.
Certainly, CO determinator, CO accountant 62 and the apparatus for predicting 60,80 of described blood generation also are equipped with all essential electronics, signal processing and computational tools.
Can can't harm the perception of HO activity and/or glucose and to carry out and often so essential, because Hb-CO sensing device 10 right and wrong are invasive.Described apparatus for predicting 80 preferably comprises display and is used to store the memorizer of described glucose level data and HO activity data.Whether this feature can be used for monitoring of diseases, for example observe patient's situation and improve or worsen.
This instrument also comprises correcting unit 31.Described correcting unit 31 comprises reference glucose sensing device 35, as the fingerstick pick off as reliable and accurate glucose sensor.Blood glucose levels with fingerstick pick off 35 based on the rule time, measure as the reference glucose level especially once a day.This reference glucose level again with the dextrose equivalent of described deduction relatively.Therefore, provide electronics, software and signal processing apparatus to described correcting unit 31, to such an extent as to carry out the mentioned comparison in front and in the deduction method, regulate and the glucose level of giving described deduction to described reference glucose level.This operation can be carried out once every day, and described correcting unit 31 also can comprise such feature, as with the LED alarm together that needs the timing flash of light with the warning user.
In addition, described correcting unit 31 can be equipped with comparison means 32, be intended to as monitoring the device that different parameters develops in time, compare between the different parameters value that obtains on the different time with the reference measurement result, wherein said reference measurement result can produce on different time with another kind of pick off or with identical pick off.Preferably, described comparison means is suitable for carrying out at least a following comparison: the ratio of the CO of the ratio of CO that the active value of described HO, described blood produce and described breathing CO, the CO that described blood produces and described calculating, the different measuring time is gone up described value and the ratio that obtains.
A kind of possible ratio is the ratio between the CO of blood generation and the CO that breathes CO or calculating, because this value has produced the CO of current generation and the ratio between the interior CO that produces of long period section.Therefore, the change that this ratio can indicate CO to produce, thereby the active change of indication HO.
Therefore, the instrument of Fig. 2 can be as hereinafter using.When the user brings into use this instrument, carry out first glucose and proofread and correct, comprise the CO measurement result that produces with described fingerstick sensor measurement reference glucose level and based on blood and measure the glucose level value and/or the HO activity value of first deduction.These two values relatively and with the dextrose equivalent of described deduction are adjusted to described reference value.After a while, when the user need carry out new glucose level mensuration, this user did not need to carry out glucose level and proofreaies and correct.
In addition, during the preset time section, daytime for example, follow-up each HO activity and/or glucose assays comprise the CO level determination based on the blood generation of the perception value of the CO level of the CO level of blood Hb-CO level, exhalation and suction, and deduction subsequently is intended to adopt all must calculation procedure and optional also mensuration glucose level value and/or HO activity with correction.
Fig. 3 is second preferred embodiment according to the present invention, is used to measure the functional diagram of the instrument of HO activity and/or blood glucose levels.This instrument comprises Noninvasive Hb-CO sensing device 10, glucose apparatus for predicting 20 and glucose level correcting unit 30.
Hb-CO sensing device 10 is suitable for measuring blood Hb-CO level, and preferably uses the Noninvasive pick off of absorption and/or spectral technique.The preferred embodiment of Hb-CO sensing device will be described in more detail with reference to Figure 4 and 5.
Glucose level apparatus for predicting 20 comprises CO level calculation device 25 and glucose level accountant 28.Electronics, signal processing and accountant are equipped with CO level calculation device 25, and it is suitable for according to described Hb-CO level, use well-known contact the between the CO of blood Hb-CO and exhalation and calculate the CO level value.Similarly, described glucose level accountant 28 also is equipped with all essential electronics, signal processing and accountant to use mentioned the getting in touch and calculate described glucose level between CO that breathes out and blood glucose levels in front.
Can can't harm the perception of glucose and to carry out and often so essential, because Hb-CO sensing device right and wrong are invasive.Described glucose level apparatus for predicting 20 preferably comprises display and is used to store described glucose level memory of data.This feature can be used for timely monitoring of blood dextrose equivalent.
This instrument also comprises glucose level correcting unit 30, needs gauged reason to be that the Hb-CO level also is subjected to other physiologic factor (as asthma) influence, and it generally causes the Hb-CO level slowly to change in time.
Described glucose level correcting unit 30 comprises reference glucose sensing device 35, as fingerstick pick off and the adjusting device 38 as reliable and accurate glucose sensor.Blood glucose levels with fingerstick pick off 35 based on the rule time, measured as the reference glucose level especially once a day.This reference glucose level again with measure through Hb-CO with after infer the dextrose equivalent comparison of the described deduction that obtains.Therefore, described adjusting device 38 is equipped with electronics, software and signal processing apparatus, to such an extent as to carry out the mentioned comparison in front and in the deduction method, regulate and the glucose level of giving described deduction to described reference glucose level.This operation can be carried out once every day, and described adjusting device 38 also can comprise such feature, as with the LED alarm together that needs the timing flash of light with the warning user.It is possible also conceiving not perception Hb-CO, the short of correction.
In addition, because environment CO level can influence blood CO level, and therefore affecting glucose level determination, this instrument also can be equipped with CO level correction device 40, is used for comprising environment CO level calculating described glucose level according to described CO level.Described CO level correction device 40 is made of together with the model building device 48 that is used for the Hb-CO level of environment CO level as described in replying is carried out modeling CO sensing device 45 (as common known detector in this area).Model building device can comprise that model changes because of the Hb-CO level of environment CO level due to changing with assessment.Possible other parameter also can take in as heart rate, breathing rate and other.Once more, be equipped with all must electronics and signal processing apparatus for described model building device 48.
Therefore, the instrument of Fig. 3 can be as hereinafter using.When the user brings into use this instrument, carry out first glucose and proofread and correct, comprise with described fingerstick sensor measurement reference glucose level, and measure the first glucose level value of inferring based on Hb-CO horizontal survey result.With these two values relatively, and with the dextrose equivalent of described deduction be adjusted to described reference value.After a while, when the user need carry out new glucose level mensuration, this user did not need to carry out glucose level in the specified time period (for example one day) and proofreaies and correct.The another kind of correction also can comprise by the simple gases detectors measure and being used for measuring and environment CO is changed the Hb-CO level of replying change the environment CO level that comprises.Can in measuring, each glucose level comprise this correction.
In addition, during the preset time section, for example one day, follow-up each glucose assays comprised blood Hb-CO level determination, infers and be intended to adopt all essential calculation procedure and the optional also mensuration glucose level value with correction subsequently.When preset time, scope was expired, the user can be cautioned and proofread and correct to carry out new glucose.
Described the preferred Hb-CO sensing device that is used for measuring tissue sample blood Hb-CO and therefore measures blood glucose levels in Fig. 4, described Hb-CO sensing device relies on the principle identical with pulse oximetry, adopts extra wavelength.
Hb-CO sensing device 10 comprises for example light source 101 of ear-lobe 104 of sensing tissue bed.Light source 101 can be the wideband light source of scope 400-1900nm, and carboxyhemoglobin has intensive absorption characteristic in described scope, and described light source preferably is uniform in given range.
Preferably, use one or more monochromaters,, preferably have identical bandwidth, have their driving electronics as laser diode.Can carry out and add different measurements.Another kind of select to be to use different monochromaters together with multiplexer and carry out single-measurement.
Light beam from light source passes the image optics instrument 103 that comprises the one or more lens that are used for focused ray.Light beam focuses on the ear-lobe 104 subsequently.When passing ear-lobe 104, light is absorbed, and in first linear approximation, absorbance is provided by Beer-Lambert law, and wherein the absorbance on setted wavelength is provided by following formula:
A λ，i＝∑ i?e i.c i.l i
E wherein iBe the absorbance of component i on wavelength X, c iThe concentration and the l that are component i are optical path lengths.
The absorbance that increases during the pulsating flow when the tremulous pulse bed is expanded because of the systole capacity increases is the tolerance that the hemoglobin composition is absorbed, and especially can obtain blood Hb-CO level from absorbance data.
Preferred wavelength is corresponding to the peak absorbance of different hemoglobin compositions, for example 530.6nm and 583nm.Overall accuracy can be improved by using several wavelength.Yet, should be understood that wavelength does not need to be in peak value, in contrast, promptly when the CO horizontal drift, the difference between the signal is most important parameter.When only using three kinds of wavelength, wavelength can be 630nm, 720nm and 900nm in exemplary.
Transillumination direct detection device 106.Detector 106 is to have uniform sensitivity in the 400-1900nm in the wave-length coverage that is used for perception Hb-CO preferably.Behind signal processing, use accountant 1008 from the signal that detects, to measure the Hb-CO level with wave filter well-known in the art and signal processing instrument.Described the alternative Hb-CO sensing device that is used for measuring sampling tissue blood Hb-CO and therefore measures blood glucose levels in Fig. 5, described Hb-CO sensing device depends on reflectance spectrometry.Preferred purpose zone is a retina, maybe can be used for screening diabetes because the Hb-CO level in the retina measured can provide prompting because of the risk of retinal damage due to the diabetes.
Hb-CO sensing device 10 comprises the light source 201 that points to eye 204.
When in eye, measuring, must consider the transparency of eye.Yet promptly there is intensive spectroscopy feature in Hb-CO in the 400-900nm scope in the transparency scope of human eye.Thereby light source 101 can be a wideband light source, in scope 400-900nm, preferably is uniform in given scope at least.Light beam from light source passes the image optics instrument 103 that comprises the one or more lens that are used for focused ray.Light beam points to eye 204 subsequently and focuses on the retina 205.Certainly, importantly the intensity of light source 201 is low does not cause damage to retina 205 to sufficient to guarantee.
Point to light source 201 once more from the light of retinal reflex.Yet spectroscope 202 is sent reflected light to detector 206.Detector 206 is to have uniform sensitivity in the 400-900nm in the wave-length coverage that is used for perception retina Hb-CO preferably, and comprises spectrometer or the optical wavelength analyzer that is used to measure the reflected light absorption spectrum.When needs, can add the signal that optoelectronics or electricity amplifier arrive with amplification detection.
The Hb-CO level comprises that by use the accountant 208 of wave filter and signal processing apparatus measures subsequently.
Should be understood that light source 101,201 can be wideband light source or depend on one group of monochromater,, preferably have identical bandwidth, have their driving electronics as laser diode.Can carry out and add different measurements.Another kind of select to be to use different monochromaters together with multiplexer with carry out single-measurement, as being to wideband light source.Can also use adjustable light sources.When considering wideband light source, can use the spectrometer device in case on several wavelength measured light intensity.
Therefore, such instrument and method are disclosed, it is active and related with blood glucose levels so that obtain the active and actual blood glucose levels of actual HO together with apparatus for predicting based on measuring controlling blood analyte levels that it is used to measure HO, wherein also preferably includes correcting unit.In very favourable mode, described instrument can realize having the degree of accuracy and the repeatability of improvement in the Noninvasive mode.

Claims (19)

1. be used to measure the instrument of blood glucose levels, described instrument comprises:
Be used to measure CO determinator that the blood of the CO level that blood produces produces and
Be used for inferring first apparatus for predicting (80) of described blood glucose levels according to the CO level that described blood produces.
2. instrument according to claim 1, the CO determinator that described blood produces comprises:
Be used for perception and breathe the breathing CO sensing device (50) of the CO level of breathing out,
Be used for perception blood carboxyhemoglobin (Hb-CO) level Hb-CO sensing device (10) and
Be used for inferring the horizontal apparatus for predicting of CO (60) that the blood of the CO level that described blood produces produces according to the CO level of described Hb-CO level and described exhalation.
3. instrument according to claim 2, the horizontal apparatus for predicting of CO (60) that described blood produces also comprises the CO accountant (62) that is used for being calculated by described blood Hb-CO leveler the CO level of calculating.
4. instrument according to claim 2, described breathing CO sensing device (62) are suitable for measuring the CO level of suction and the CO level of exhalation.
5. instrument according to claim 4, the CO level that described blood produces are the functions of the CO level of the CO level of the CO level of described exhalation, described suction and described calculating.
6. be used to measure the instrument of blood glucose levels, described instrument comprises:
Be used for perception blood carboxyhemoglobin (Hb-CO) level Hb-CO sensing device (10) and
Be used for inferring second apparatus for predicting (20) of described blood glucose levels based on described Hb-CO level.
7. instrument according to claim 6, described second apparatus for predicting comprises:
Be used for calculating the CO level calculation device of carbon monoxide (CO) level according to described Hb-CO level.
8. instrument according to claim 7, described second apparatus for predicting also comprises the glucose level accountant that is used for calculating according to the CO level of described calculating described blood glucose levels.
9. instrument according to claim 8 also comprises CO level correction device, is used for comprising environment CO level calculating described glucose level according to the CO level of described calculating.
10. instrument according to claim 9, described CO level correction device comprises
Be used for perception environment CO level the CO sensing device and
Be used for model building device that the Hb-CO level that responds to described environment CO level is carried out modeling.
11. instrument according to claim 2, described Hb-CO sensing device comprises:
Be used for irradiation unit with a plurality of wavelength illumination health parts,
Be used to collect transillumination and/or catoptrical gathering-device and
Be used to calculate the Hb-CO accountant of the Hb-CO level that responds to transmission, emission and/or intensity of reflected light.
12. instrument according to claim 11, the described Hb-CO sensing device that is used for the described Hb-CO level of perception also comprises:
Be used for irradiation unit with a plurality of wavelength illumination health parts,
Be used to collect transillumination and/or catoptrical gathering-device,
Be used for according to separate from the band of described a plurality of wavelength transillumination and/or catoptrical light-dividing device and
Be used for calculating the Hb-CO accountant of described Hb-CO level according to isolating transmitted intensity/intensity of reflected light.
13. instrument according to claim 11, described a plurality of wavelength are in the about 950nm scope of about 450nm-.
14. instrument according to claim 1, also comprise and be used to proofread and correct described blood glucose levels and/or the active correcting unit of described HO that obtains by inferring, described correcting unit comprises the reference glucose sensing device that is used for perception reference glucose level and is used for the comparison means of comparison in the described blood glucose levels value of different measuring time acquisition.
15. instrument according to claim 14, described comparison means is suitable for carrying out at least a following comparison: the ratio of the CO of CO that described blood produces and the ratio of the CO of described exhalation, the generation of described blood and the CO of described calculating, described ratio obtained in the different measuring time.
16. be used for non-invasively measuring the method for blood glucose levels, comprise step:
Measure CO level that blood produces and
Infer described glucose level according to described Hb-CO level.
17. method according to claim 16 infers that the step of described glucose level comprises the following steps:
Breathing CO level during perception is breathed,
Perception blood carboxyhemoglobin (Hb-CO) level and
Infer the CO that the active and/or described blood of described HO produces according to described Hb-CO level and described breathing CO level.
18. be used for non-invasively measuring the method for blood glucose levels, comprise step:
Perception blood carboxyhemoglobin (Hb-CO) level and
Infer described glucose level according to described Hb-CO level.
19. method according to claim 18 infers that the step of described glucose level comprises the following steps:
According to described Hb-CO level calculation carbon monoxide (CO) level and
The described glucose level of CO level calculation according to described calculating.
CNA2007800141370A 2006-04-21 2007-04-18 Non-invasive glucose sensor Pending CN101553160A (en)

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